The present invention relates to macromolecular drug complexes and to the administration of compositions containing the macromolecular drug complexes to individuals. More particularly, the present invention relates to a drug delivery system comprising a macromolecular drug complex containing a therapeutic agent that is noncovalently bound, i.e., is complexed, to a polymer having a plurality of acid moieties. The macromolecular drug complex is incorporated into a microemulsion to provide the drug delivery system. The complex is prepared by interacting the polymer and a therapeutic agent, such as human growth hormone, in an aqueous medium. Depending on the physicochemical properties of the polymer and therapeutic agent, the resulting macromolecular drug complex either is water soluble or separates from the aqueous medium as a solid precipitate. The macromolecular complex is incorporated into a microemulsion for administration of the therapeutic agent.
It is well known that modern day drugs are very efficacious with respect to treating acute and chronic diseases. However, several diseases, and especially chronic diseases, are associated with complications that are not treated by administration of the drug.
For example, the standard treatment for diabetes is administration of insulin. An individual suffering from diabetes does not produce sufficient insulin, and hence the individual cannot burn and store glucose. Diabetes cannot be cured, but diabetes can be treated by periodic injections of insulin. FIG. 1 shows that serum insulin levels rise from a low fasting value to a peak after about 30 to 60 minutes, then fall back to a low value after about 120 minutes. In mild diabetics, the rise in serum insulin is lower compared to normal individuals. In severe diabetics, no insulin is produced, and the rise in serum insulin levels is negligible. As a result, excess glucose accumulates in the blood of a diabetic, which can result, for example, in a loss of weight and loss of strength.
However, insulin injections to treat diabetes do not treat, or alleviate, the serious vascular complications associated with diabetes, including nephropathy, retinopathy, neuropathy, heart disease, and reduced blood circulation in the limbs, i.e., xe2x80x9cdiabetic foot,xe2x80x9d that can lead to gangrene. Another disadvantage with respect to the present therapeutic compositions used to treat diabetes is that insulin must be injected. Insulin cannot be administered orally because insulin is destroyed by the strong acid conditions of the stomach.
Therefore, it would be advantageous to develop a method of both treating a disease, and preventing or reversing complications associated with the disease. It also would be advantageous to develop easier methods of administering a drug to treat the disease. As set forth in detail hereafter, the present invention is directed to macromolecular drug complexes, to compositions containing the complexes, and to use of the complexes to reduce, eliminate, or reverse complications associated with a disease. The present invention is further directed to improved drug delivery systems for administering difficult to administer drugs, like insulin and human growth hormone.
With respect to diabetes, glycosaminoglycans (GAGs) are a class of negatively charged, endogenous polysaccharides composed of repeating sugar residues (uranic acids and hexosamines). GAGs have been shown to bind a variety of biological macromolecules, including connective tissue macromolecules, plasma proteins, lysosomal enzymes, and lipoproteins. In addition, exogenous GAGs have been shown to bind to the cell surfaces of a variety of different cell types, including liver cells (hepatocytes), fibroblasts, and importantly, endothelial cells. Exogenous GAGs, therefore, can be internalized. Furthermore, GAGs have been implicated in the regulation of cell proliferation and in cell-cell communication, shown to interact with cell-surface receptors (cell adhesion molecules), and shown to modify the behavior of cells in culture. In addition, GAGs were shown to be highly potent, selective inhibitors of HIV replication and giant cell formation.
GAG-receptor interactions are characterized by the formation of noncovalent, self-assembling macromolecular complexes. These transient, interpolyelectrolyte complexes mediate many biological functions including enzyme-substrate binding, antigen-antibody interactions, leukocyte-endothelial cell adhesion events, drug-receptor binding, and protein-protein interactions. Furthermore, secondary binding forces, such as hydrogen bonds, van der Waals forces, and hydrophobic interactions, govern interpolyelectrolyte formation, and, ultimately, influence the resulting pharmacologic response to the complex.
G. Gambaro et al., Kidney Int., 46, pages 797-806 (1994) discloses that exogenously administered GAGs have a favorable effect on morphological and functional renal abnormalities in diabetic rats, and appear to revert established diabetic renal lesions. Furthermore, D. M. Templeton, Lab. Invest., 61(2), pages 202-211 (1989) and C. W. Marano et al., Invest. Ophthalmology Vis. Sci., 33(9), pages 2619-2625 (1992) disclose that diabetic patients have a decreased glycosaminoglycan content in glomerular basement membranes. Additionally, an increase in total GAG serum levels in diabetic patients was disclosed in K. Olczyk et al., Acta Biochimica Polonica, 39, pages 101-105 (1992). The authors observed an increase in protein-bound GAGs, such as keratan sulfate, hyaluronic acid, heparin sulfate, and heparin in diabetic patients. Gambaro et al. also discloses an increase in the urinary excretion rate of GAGs from insulin-dependent diabetic patients.
Therefore, publications show that glycosaminoglycans play an important, yet unexplained, role in the vascular changes associated with life-long insulin therapy. In particular, administration of GAGs to diabetic animals has inhibited or reversed some vascular abnormalities. The publications also strongly suggest that exogenous insulin plays a role in elevating the level of GAGs in the urine and serum of diabetic patients. Furthermore, the publications clearly show that glycosaminoglycans bind to a multitude of biological macromolecules, including proteins.
These observations appear to suggest utilizing glycosaminoglycans as an adjuvant to insulin therapy. However, GAGs are anticoagulants and long term use of GAGs with insulin may thin the blood of an individual. The risks associated with a long-term use of GAGs also are unknown. Although GAGs have been used as therapeutic agents, e.g., heparin, GAGs have not been used for extended periods of time, or for the treatment of a chronic disease or condition, like diabetes. The present invention is directed to drug complexes and compositions containing the drug complexes, that provide the benefits of a drug GAGs complex, but that avoid the disadvantages associated with long term administration of a GAG compound.
Similar to endogenous GAGs complexes discussed above, GAGs and other naturally occurring and synthetic anionic polymers have been complexed with various therapeutic agents to provide a macromolecular drug complex, which then is incorporated into a microemulsion for administration to an individual, e.g., by oral or parenteral delivery, for example. The present drug delivery system makes it possible to regulate the pharmacologic response, and the route of administration of many drugs, by a judicious selection of polymer ionically complexed to the drug.
The present invention is directed to a drug delivery system comprising a drug complexed with a polymer having a plurality of acid moieties. The macromolecular drug complex is incorporated into a microemulsion to provide a drug delivery composition of the present invention.
The macromolecular drug complexes treat the underlying disease or condition, e.g., insulin to treat diabetes or human growth hormone to treat dwarfism, hypopituitarism, hypercholesterolemia, hypertension, depression, muscle wasting, osteoporosis, insomnia, menopause, impotence, as well as other conditions commonly associated with aging, and complications associated with the disease or condition, e.g., prevent or reverse the vascular problems associated with diabetes. The present macromolecular drug complexes can be water soluble or water insoluble at neutral pH. Therefore, the macromolecular drug complex can be administered in a variety of dosage forms.
More particularly, the present invention is directed to a drug delivery composition comprising a microemulsion incorporating a macromolecular drug complex. The macromolecular drug complex contains a drug and a polymer having a plurality of acid moieties and a weight average molecular weight (Mw) of about 1,000 to about 50,000. In accordance with an important aspect of the present invention, the drug contains at least one quaternary ammonium nitrogen atom for binding to, and complexing with, the polymer. Preferred drugs are polypeptides or proteins. The polymer contains a plurality of acid moieties for complexing with the drug. The acid moiety can be a carboxyl group, sulfate group, sulfonate group, phosphonic acid group, phosphoric acid group, phenolic group, or a similar acid moiety.
Another aspect of the present invention is to provide a macromolecular drug complex wherein the polymer is a naturally occurring polymer or a synthetic polymer.
Another aspect of the present invention is to provide a macromolecular drug complex containing a drug and a polymer in a weight ratio of drug to polymer of about 10 to about 90 to about 90 to about 10.
Yet another aspect of the present invention is to incorporate the macromolecular drug complex into a microemulsion, wherein the drug complex can be administered to an individual in a liquid form.
Another aspect of the present invention is to provide a microemulsion composition comprising a macromolecular drug complex that can be administered to an individual to treat an acute or chronic disease or condition, and to alleviate, eliminate, or reverse complications associated with the disease.
Another aspect of the present invention is to provide a microemulsion composition comprising a macromolecular drug complex remains intact and does not dissociate immediately after administration, and that are capable of releasing the drug in vivo to treat a disease.
Still another aspect of the present invention is to provide a composition containing a macromolecular drug complex wherein the drug is human growth hormone, insulin, methotrexate, isoniazid, chloroquine phosphate, a polypeptide, or a protein.
Another aspect of the present invention is to provide a microemulsion containing a macromolecular drug complex containing human growth hormone and a naturally occurring polymer, like heparin.
Yet another aspect of the present invention is to provide a microemulsion comprising a macromolecular growth hormone complex that treats dwarfism, hypopituitarism, hypercholesterolemia, hypertension, depression, muscle wasting, osteoporosis, insomnia, menopause, impotence, as well as other conditions commonly associated with aging.
One other aspect of the present invention is to provide alternate routes of administration for the safe, easy, and effective delivery of a therapeutic agent, especially to provide an oral route of administration for insulin, human growth hormone, and other drugs.
These and other novel features and aspects of the present invention will become apparent from the following detailed description of the preferred embodiments.